The present Invention relates to a method for treating mammals (such as, e.g., humans) in need thereof with a novel controlled release pharmaceutical composition for oral use containing midodrine and/or its active metabolite desglymidodrine together with a relatively fast onset composition of midodrine and/or its active metabolite desglymidodrine. The present invention also relates to a kit comprising a controlled release composition, e.g. intended for administration once or twice daily, together with one or more relatively fast onset compositions for supplemental and individual administration.
The invention also relates to a pharmaceutical composition comprising comprising midodrine (ST 1085) or a pharmaceutically acceptable salt thereof and/or its active metabolite desglymidodrine (ST 1059) or a pharmaceutically acceptable salt thereof, the composition being adapted to provide midodrine and/or desglymidodrine in such a manner that a relatively fast therapeutically effective concentration of desglymidodrine is obtained after administration of the composition.
The novel controlled release compositions are designed to release midodrine and/or desglymidodrine after oral intake in a manner which enables absorption to take place in the gastrointestinal tract so that a relatively fast peak plasma concentration of the active metabolite desglymidodrine is obtained followed by a prolonged and relatively constant plasma concentration of desglymidodrine. However, the patient may due to individual needs or because of activities during the day experience situations where an increase in the plasma concentration is needed for an optimal treatment regimen. Therefore, the patient may on an individual basis supply the controlled release composition with one or more administrations of a quick release composition or another composition providing a relatively fast onset.
The indications of midodrine include symptomatic orthostatic hypotension, orthostatic intolerance, symptomatic hypotension (e.g. hypotension associated with infections, the convalescent period, surgical operations, delivery, changes in the weather as well as what is called xe2x80x9cdifficulties in getting started in the morningsxe2x80x9d), as well as in the control of hypotensive side effects of hypnotics and psychotropics. Futhermore, midodrine is expected to be effective in the treatment of urinary incontinence. Many of these indications call for a very individual treatment regimen where a basic xe2x80x9call dayxe2x80x9d treatment supplied with one or more fast onset formulations are very beneficial.
In another aspect, the invention relates to a method for treating hypotension and/or urinary incontinence, the method comprising administration to a patient in need thereof of an effective amount of midodrine and/or desglymidodrine in a controlled release composition according to the invention together with one or more fast onset compositions comprising an effective amount of midodrine and/or desglymidodrine.
One of the advantages of the invention is that the controlled release composition provides a base line plasma concentration, which during most of the day is therapeutically effective. When a higher concentration is needed, only a minor supply of active drug substance is necessary to obtain a very fast relief from symptoms. If the constant base line plasma concentration was absent, it would be necessary to use a relative higher fast onset dose to reach the high therapeutically effective level. The high therapeutically effective level may be due to individual circumstances in the patient or may be a consequence of physical routines and/or the nature of the underlying disease. The situations and symptoms are often well recognized and experienced by the patient himself. The kit according to the present invention is a superior tool for obtaining an optimal treatment with a minimum of active drug substance.
The novel compositions are also designed for administration once or twice daily, preferably once daily, i.e. a therapeutically effective concentration of desglymidodrine is maintained for a period of at least 10-16 hours followed by a wash out period of about 8-12 hours in order to avoid the well-known midodrine related side effect with respect to supine hypertension. In the present context a therapeutically effective concentration of desglymidodrine is defined as a plasma concentration of desglymidodrine of at least about 3 ng/ml such as, e.g. at least about 3.2 ng/ml, at least about 3.5 ng/ml, at least about 3.7 ng/ml, at least about 4.0 ng/ml, at least about 4.2 ng/ml, at least about 4.5 ng/ml, at least about 4.7 ng/ml or at least about 5 ng/ml.
Controlled release midodrine compositions are known from the prior art, e.g. U.S. Pat. No. 5,128,144 (Korsatko-Waabnegg et al.), EP-B-0 164 571 (CL Pharma Aktiengesellschaft) and AT-8-B-383 270 (Chemie Linz Aktiengesellschaft). However, in none of these documents are any compositions intended for less frequent administration such as, e.g., once or twice daily and furthermore, there is no indication of absorption of midodrine (or its active metabolite) from the colon.
Midodrine is a prodrug, which is activated within the human body by an enzymatic hydrolysis to release the therapeutically active metabolite desglymidodrine. Desglymidodrine acts by a stimulation of xcex11 receptors. Midodrine is used in the treatment of symptomatic orthostatic hypotension. Disorders causing orthostatic hypotension are
Generalized Primary Autonomic Failure
Pure autonomic failure or idiopathic orthostatic hypotension (Bradbury-Eggleston syndrome)
Pure autonomic failure with multiple-system atrophy or Shy-Drager syndrome
Acute pandysautonomia (panautonomic neuropathy)
Familial dysautonomia (Riley-Day syndrome)
Partial Primary Autonomic Failure
Dopamine E-hydroxylase deficiency
Postural orthostatic tachycardia syndrome (length-dependent autonomic neuropathy)
Monoamine oxidase deficiency
Pure vasomotor failure
Disorders of Idiopathic Orthostatic Intolerance
Postural orthostatic tachycardia syndrome
Mitral valve prolapse
Due to prolonged bed rest or space flight
Due to asthenic habitus
Disorders of the Central Nervous System
Tumors (hypothalamic, parasellar, posterior fossa)
Multiple cerebral infarcts
Wernicke""s encephalopathy
Tabes dorsalis
Traumatic and inflammatory myelopathies
Parkinson""s disease
Hereditary system degenerations
Syringomyelia
Dysautonomia of advanced age
Multiple sclerosis
Systemic Diseases with Autonomic Neuropathy
Botulism
Diabetic neuropathy
Primary systemic amyloidosis
Guillain-Barrxc3xa9syndrome
Porphyria
Lambert-Eaton myasthenic syndrome
Paraneoplastic autonomic neuropathy
Uremic neuropathy
Connective tissue disease
Tangier and Fabry""s diseases
Vincristine and heavy metal neuropathies
Leprosy
B12 deficiency
4 Chronic Chagas"" disease
Propafenone neuropathy (16)
Endorcine-metabolic Disorders
Primary and secondary adrenocortical insufficiency
Pheochromocytoma
Marked potassium depletion
Severe hypoaldosteronism
Latrogenic Causes
Antihypertensive drugs (xcex94-methyldopa, guanethidine, prazosin, E blockers)
Psychotropic drugs (phenothiazines, butyrophenones)
Antiparkinsonian drugs (Sinemet, Parlodel)
Vasodilator drugs (nitrates)
Certain illicit drugs (marijuana)
Thoracolumbar sympathectomy
Disorders with Diminished Cardiac Output
Reduced intravascular volume
Acute and chronic blood loss
Fluid loss due to vomiting, diarrhea, diuretics
Gastrectomy with the dumping syndrome
Salt-losing nephropathy
Altered capillary permeability
Impaired venous return
Severe varicose veins
Venous obstruction (late pregnancy)
Reflex and pharmacologic vasodilatation
Muscle wasting and prolonged recumbency
Intrinsic cardiac disease
Myocardial infarct
Arrhythmias
Restrictive pericardial/myocardial diseases
Miscellaneous Causes
Hyperbradykinnism
Chronic renal hemodialysis
Anorexia nervosa
Reduced aortic compliance
Mastocytosis
Baroreflex failure.
Furthermore, midodrine may be used in disorders retrograde ejaculation; disorder of semen ejaculation, or to attenuate symptoms of chronic orthostatic hypotension due to autonomic failure in patients with Bradbury-Eggleston, Shy-Drager syndromes, diabetes mellitus disease and Parkinson""s disease.
Midodrine is approved in a variety of European and overseas countries including the U.S.A. mainly for the treatment of symptomatic orthostatic hypotension. FDA has recommended a dosing of midodrine of up to 10 mg 3 times daily for the treatment of hypotension. According to FDA, the latest dose must not be given later than 6 pm for safety reasons in order to avoid or reduce the risk of supine hypertension. Other countries recommend that the latest dose must not be given later than 4 hours before bedtime.
Midodrine for use in stress urinary incontinence is a very promising use with a tremendous market potential also due to the ageing population. Current conservative therapeutic approaches are xcex1-sympathomimetics, pelvic floor exercises and estrogens, or surgery, which are rather complementary than competitive.
Due to the rather short half-life of the active metabolite of approximately 3 hours midodrine normally must be administered 2-4 times daily. Considering the chronic nature of the diseases in question, which requires a long term treatment as well as the correlation between plasma levels and the incidence and severity of adverse events, the development of a controlled release form is highly desired.
It has now been found that absorption takes place through the whole gastrointestinal tract, Thus, it has been found that when midodrine reaches the colon (about 8 hours after intake of a single unit capsule containing midodrine) the prodrug midodrine is not measured in plasma at least not at a therapeutic level while the extent of absorption of the active metabolite is identical to that of a solution. In other words, with respect to absorption from the colon it has been found that it is not midodrine, which is measured after oral intake of midodrine but instead it is the active metabolite desglymidodrine itself.
After colon absorption a maximum plasma concentration of desglymidodrine is found to take place at approximately 3 hours after application, i.e. tmax corresponds to approx. 3 hours. In contrast thereto, a tmax of about 1-2 hour for desglymidodrine is observed after oral intake of midodrine and the corresponding value for midodrine itself is a tmax of about 30 min.
The finding that midodrine is converted to the active metabolite before or during absorption from the colon is of importance with respect to the present invention. A further important issue is the fact that FDA has recommended that the latest dose of midodrine is taken not later than 6 pm for safety reasons, thus a wash out period through the night is desirable.
Based on the above findings and the therapeutic needs, the present inventors have developed a kit containing at least two different parts each containing midodrine and/or its active metabolite desglymidodrine. In the present context the term kit is intended to include
i) a package comprising at least a first and a second pharmaceutical composition, wherein the first composition is designed to release the active drug substance relatively fast in order to obtain a relatively fast onset of the therapeutic effect and the second composition is in the form of a controlled release composition (cf. a co-pending patent application by the same inventors) which is designed to give a release pattern as described below in order to utilize the possibility of having the active drug substance absorbed not only in the upper part of the gastrointestinal tract but also during its passage through colon, the first and the second composition may be of the same kind, e.g. in the form of tablets or capsules or they may be in the form of two different types of pharmaceutical compositions e.g. the first composition may be in the form of plain tablets or a nasal spray and the second composition may be in the form of controlled release tablets or capsules, and
ii) a pharmaceutical composition which include a first and a second part, wherein the first part is designed to release the active drug substance relatively fast in order to obtain a relatively fast onset of the therapeutic effect and the second part is a controlled release part (cf. a co-pending patent application by the same inventors) which is designed to give a release pattern as described below in order to utilize the possibility of having the active drug substance absorbed not only in the upper part of the gastrointestinal tract but also during its passage through colon, and the first and the second part are presented in the form of a single composition such as, e.g. in the form of a tablet, a capsule (e.g. containing pellets which may be the same or different), sachets, powders etc
In the following details on the controlled release compositions are given. Whenever relevant, the initial relase described for the controlled release composition also applies for the composition or part of the composition of the kit intended for a relatively fast release of the active substance.
Based on the above findings, the present inventors have developed a pharmaceutical kit comprising as one part or one composition a controlled release composition for oral use containing midrodrine and/or desglymidodrine and the composition is designed to the release of midodrine and/or desglymidodrine in at least the following consecutive steps:
The first part or first composition of the kit according to the invention (i.e. the part or composition giving rise to a relatively fast onset of midodrine and/or desglymidodrine) releases the active drug substance as described in step 1 above. Whenever relevant, details relating to such a first step including the relevant formulation techniques as well as the relevant pharmacokinetic parameters (absorption, metabolism and elimination) also apply to the first part or first composition of the kit.
The above release pattern is contemplated in order to obtain the desired plasma concentration of desglymidodrine during day and night after administration orally once daily. Thus, the release pattern above is based on the following requirements with respect to the plasma concentration of desglymidodrine:
1. an initial rise in plasma concentration until a peak concentration is reached (in the present Context xe2x80x9ca peak concentrationxe2x80x9d is intended to mean a peak value, a shoulder value or a plateau value in the concentration),
2. a relatively constant plasma concentration of desglymidodrine for approximately about 4.5-14 hours such as, e.g., about 5-14 hours, about 6-14 hours, about 7-14 hours, about 8-13 hours, about 9-13 hours, about 10-14 hours, about 10-13 hours, or such as, e.g. for at least about 4.5 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, or at least about 11 hours. In some case, the constant plasma concentration of desglymidodrine may last for at least about 12 hours, at least about 13 hours or at least about 14 hours,
3. a decline in plasma concentration with a half-life of e.g. about 3-4 hours to avoid supine hypertension but other half-lives may also be acceptable e.g. reflecting a continous release of midodrine and/or desglymidodrine from the composition.
Compositions according to the invention are therefore designed based on the following principle; the term xe2x80x9cpartxe2x80x9d is intended to include a separate part within the composition (the composition may contain pellets of e.g. two different types or an integrated element of the composition, e.g. a multilayer tablet):
1. The composition contains a part intended for relatively fast release of midodrine and/or desglymidodrine
2. The composition contains a part intended for prolonged release of midodrine and/or desglymidodrine, and the prolonged release is intended to last for at least about 7-8 hours.
3. The composition contains a part intended to release midodrine and/or desglymidodrine relatively fast when the composition (or the disintegrated parts of the composition) reaches the colon, i.e. about 6-10 hours such as, e.g., about 8 hours after oral administration.
4. The release of midodrine and/or desglymidodrine from a composition according to the invention is terminated at the most about 12-16 hours after administration in order to obtain a wash out period during night.
In one aspect the kit according to the invention comprises a controlled release pharmaceutical composition for oral use comprising midodrine (ST 1085) or a pharmaceutically acceptable salt thereof and/or its active metabolite desglymidodrine (ST 1059) or a pharmaceutically acceptable salt thereof, the composition being adapted to release midodrine and, when present, desglymidodrine in such a manner that a relatively fast peak plasma concentration of desglymidodrine is obtained and that a therapeutically effective plasma concentration of desglymidodrine is maintained for at least about 9 hours such as, e.g. at least about 10 hours, at least about 11 hours, at least about 12 hours, at least about 13 hours, or at least about 14 hours.
More specifically, a relatively fast peak (or shoulder or plateau) plasma concentration of desglymidodrine is obtained about 15 min-6 hours such as, e.g. about 0.5-6 hours, about 1-6 hours, about 2-5.5 hours, or about 2.5-5.2 hours after oral administration of a composition according to the invention.
As mentioned above, it is important to keep the plasma concentration at a relatively constant level and, therefore, the plasma concentration of desglymidodrine after administration of midodrine and/or desglymidodrine is preferably maintained at a therapeutically active level for about 5-16 hours, such as, e.g., about 6-16 hours, about 7-16, about 8-15, about 9-15, about 10-15, about 11-14, about 12-14 or about 13, or least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, at least about 12 hours, at least about 13 hours, at least about 14 hours, at least about 15 hours or at least about 16 hours.
In the present context, the term xe2x80x9crelatively constant levelxe2x80x9d means that n is nxc2x160%, such as, e.g., nxc2x150% or nxc2x140% and wherein n is the plasma concentration in ng/ml and monitored in a healthy person. The determination of the xe2x80x9crelatively constant levelxe2x80x9d is performed as described in Example 15 herein.
It should be noted that the initial fast release from the controlled release composition may be supplemented with or replaced by a separate fast onset composition (i.e. a first composition of the kit) resulting in a peak plasma concentration within the period stated for the initial rise in plasma concentration. A separate fast onset composition gives a flexibility with respect to the dose administered, i.e. if needed a relatively low or a relatively high dose of the active drug substance may be administered dependent on the patient""s needs. Thus, in other aspects the invention relates to such relatively fast onset compositions.
In principle, relevant active drug substances for use in a composition according to the invention are any drug substance for which a dissolution pattern as described below is of relevance. The most interesting drug substances in this respect and with respect to treatment of orthostatic hypotension and urinary incontinence are the prodrug midodrine and its active metabolite desglymidodrine. In a preferred aspect, a composition according to the invention includes midodrine alone, desglymidodrine alone, or a combination of midodrine and desglymidodrine. Of course such compositions may also contain other active drug substances, if relevant.
Generally, after oral administration of a composition according to the invention containing midodrine, a peak plasma concentration of midodrine is obtained 15-90 min after oral administration. Moreover, the plasma concentration of midodrine after oral administration is maintained at a relatively constant level for about 0.7-4 hours such as, e.g. at least about 0.7 hours, at least about 1 hour, at least about 2 hours, at least about 3 hours, or at least about 4 hours.
To this end, the term xe2x80x9crelatively constantxe2x80x9d is intended to mean m is mxc2x160%, such as, .e.g., mxc2x150% or mxc2x140% and wherein m is the plasma concentration in ng/ml and monitored in a healthy person The determination of the xe2x80x9crelatively constant levelxe2x80x9d is performed as described in Example 15 herein.
The relatively fast onset compositions in a kit according to the invention may be in the form of tablets such as, e.g, conventional tablets, melt tablets, coated tablets, buccal tablets, capsules, sachets, drops, dispersions, solutions, emulsions, suspensions, gels, hydro gels, nasal compositions such as, e.g. nasal spray or nasal powder compositions, compositions for pulmonary administration such as, e.g inhalators, chewing compositions such as, e.g., chewing gum, etc. Especially suited compositions for a fast onset is compositions in fluid form and in the form of nasal compositions as well as quick release tablets.
In the following further details on a controlled release composition of the kit according to the invention is given.
Examples on relatively fast onset compositions are illustrated in the Examples.
Dissolution Requirements
As described in the following, a target plasma profile and release profile can be designed for the controlled release composition or the controlled release part of the kit comprising midodrine and/or the active metabolite desglymidodrine.
Based on our knowledge of the plasma profile of a midodrine solution and obtained Cmax values for inactive midodrine and active metabolite desglymidodrine after tablet administration a target in vivo profile has been estimated (FIGS. 1 and 2).
The target profile is based on the findings discussed above and the assumption that it would be preferable to have a fast onset of action and a relatively stable plasma level for 8-11 hours and thereafter to eliminate the drug during the night phase to avoid supine hypertension.
The presumptions made in estimating this target profile were:
i) a fast peak and an effective concentration of the active metabolite for approximately 14 hours are desired from a therapeutic point of view (FDA recommendation: latest dose at 6 pm),
ii) that the first fraction of the composition should have an absorption rate similar to that of plain tablets,
iii) that the peak concentration should not be higher than the peak concentration observed after administration of 33% of the total dose in the form of a plain tablet,
iv) that the plateau level for midodrine should last for approximately 8 hours and for desglymidodrine for approximately 11 hours,
v) that the drug reaches colon after approximately 8 hours,
vi) that midodrine is absorbed in the colon with a tmax of 3 hours (desglymidodrine) compared to a tmax of xc2xd hour (midodrine) when absorbed in the small intestine,
vii) that midodrine will not be measured after the colon absorption as midodrine but only as desglymidodrine,
viii) that tmax of desglymidodrine will appear 1 hour after oral administration of midodrine,
ix) that t1/2 for midodrine is xc2xd-1 hour and for desglymidodrine 3-4 hours, and
x) that Cmax after 7.5 mg midodrine is approximately 11 ng/ml (midodrine) and approximately 3.75 ng/ml (desglymidodrine).
Based on the fact that midodrine plain tablets are dosed from 2.5 mg-10 mg up to 4 times daily and that an individual variation in need for midodrine is known, the level of the target plasma profile may vary a factor 0.1-5. The shape of the profile is more important than the exact level of plasma concentrations.
The estimated target plasma profile has been deconvoluted with plasma concentrations from an oral solution for both midodrine and desglymidodrine to give an estimated in vivo dissolution profile (FIGS. 3 and 4). All data were normalised to a dose of 7.5 mg before deconvolution. In the deconvolution a time interval of 0.5 hours was employed (cf: Langenbucher F., Mxc3x6ller H. Correlation of in vito drug release with in vivo response kinetics. Part I: mathematical treatment of time functions. Pharm. Ind.1983;45:623-8, and Langenbucher F., Mxc3x6ller H. Correlation of in vitro drug release with in vivo response kinetics. Part II: Use of function parameters. Pharm. Ind. 1983;45:629-33).
The presumption in making this deconvolution was that the daily dose of midodrine is the same irrespective of whether the new CR composition or a plain tablet or a solution were administered.
Using this deconvolution, the in vitro dissolution profile for a composition according to the invention is estimated.
Presumptions for this Estimation are
i) that the in vitro-in vivo correlation will be 1:1
ii) that it is possible with the new invention to make a product with essential 100% release after 10-14 hours
iii) that midodrine is absorbed as such or as the active metabolit through the whole gastrointestinal tract (including colon) in order not to loose any amount of active drug substance ready for absorption into the circulatory system.
Target Release in vitro Profile Estimated as Described Above
In order to reflect the second rise in release of midodrine corresponding to the time when the composition reaches the colon, the following target profile is also relevant:
As apparent from the above, an initial relatively fast release of midodrine is suitable and after about 6-8 hours a second rise in release should be observed. Accordingly, a target release rate profile is as follow (the release rate is given in % dissolved/hour):
about 35%/hour about 30 min after start of the dissolution test,
about 12%/hour about 1 hour after start of the dissolution test,
about 6%/hour about 2 hours after start of the dissolution test,
about 7%/hour about 3 hours after start of the dissolution test,
about 6.5%/hour about 4 hours after start of the dissolution test,
about 6.5%/hour about 5 hours after start of the dissolution test,
about 7.5%/hour about 6 hours after start of the dissolution test,
about 12%/hour about 7 hours after start of the dissolution test,
about 10%/hour about 8 hours after start of the dissolution test,
about 3.5%/hour about 9 hours after start of the dissolution test
about 2%/hour about 10 hours after start of the dissolution test
about 1%/hour about 12 hours after start of the dissolution test.
In FIG. 5 is given a target dissolution profile and a target release rate curve.
As dissolution test any acceptable method may be applied, preferably a method according to USP or Ph.Eur. Throughout the examples 1, 3-10, the following method has been employed: the in vitro dissolution method according to USP and Ph.Eur. employing dissolution apparatus 2 (paddle), 100 rpm, 0.1 N hydrochloric acid as dissolution medium and a temperature of 37xc2x0 C. It is contemplated that other dissolution media may be suitable as well as another rotation speed.
Reference is given to the claims herein where further details concerning the dissolution patterns and the release rates of a controlled release composition of a kit according to the invention are given.
With respect to the release of midodrine and/or desglymidodrine from the relatively fast onset composition or part of the kit, the following applies:
Tablets (plain): disintegration time less than 5 min and often less than 5 min such as, e.g. 1-3 min.
Sublingual, buccal and melt tablets: by mould technique: disintegration time less than about 30 sec such as, e.g. about 2-10 sec; by compression or compacting, disintegration time less than about 4 min such as, e.g. about 2-3 min.
Other compositions normally contain midodrine and/or desglymidodrine in dissolved form. Thus, no retardation of the release of the active drug substance from such compositions is expected.
Specific Embodiments of Interest are as Follows
Controlled release compositions of the kit according the invention wherein the release pattern of midodrine from the controlled release compositionxe2x80x94when tested in vitro using Dissolution Method I or II described in the Experimental part herein and employing a basket according to USP and Ph. Eur, 100 rpm, 600 ml 1 N hydrochloric acid as dissolution medium and a temperature of 37xc2x0 C.xe2x80x94is:
1-15% w/w is released from the composition within the first 30 min after start of the test,
10-35% (25%) w/w is released about 30 min after start of the test,
15-40% (35%) w/w is released about 1 hour after start of the test
20-50% (39%) w/w is released about 2 hours after start of the test,
20-55% (47%) w/w is released about 3 hours after start of the test,
25-75% such as, e.g., 25-65% (53%) w/w is released about 4 hours after start of the test,
30-74% (66%) w/w is released about 6 hours after start of the test,
40-85% (80%) w/w is released about 8 hours after start of the test,
65-100% (93%) w/w is released about 10 hours after start of the test,
90-110% (100%) w/w is released about 12 hours after start of the test.
A release pattern of midodrine from a controlled release composition of the kit according to the inventionxe2x80x94when tested in vitro using Dissolution Method III or IV described herein and employing a basket according to USP and Ph. Eur, 100 rpm, a first dissolution medium with a pH of about 1.0 for the first 2 hours of the testing followed by a second dissolution medium with a pH of about 6.0 for the next 5.5 hours and finally a third dissolution medium with a pH of about 7.5 until the end of the testing, and a temperature of 37xc2x0 C.xe2x80x94may also be:
1-15% w/w is released from the composition within the first 30 min after start of the test,
10-35% (25%) w/w is released about 30 min after start of the test,
15-40% (35%) w/w is released about 1 hour after start of the test
20-50% (39%) w/w is released about 2 hours after start of the test,
20-55% (47%) w/w is released about 3 hours after start of the test,
25-75% such as, e.g., 25-65% (53%) w/w is released about 4 hours after start of the test,
30-74% (66%) w/w is released about 6 hours after start of the test,
40-95% such as, e.g., 45-85% (80%) w/w is released about 8 hours after start of the test,
65-100% (93%) w/w is released about 10 hours after start of the test,
75-110% (100%) w/w is released about 12 hours after start of the test.
Another release pattern of midodrine from a controlled release composition of a kit according to the present inventionxe2x80x94when tested in vitro employing any of Dissolution Method I, II, III or IV as described herein,xe2x80x94is as follows (xc2x130% w/w such as, e.g., xc2x125%, xc2x120%, xc2x115% or xc2x110% of the values stated below):
about 25% w/w is released about 30 min after start of the test,
about 35% w/w is released about 1 hour after start of the test,
about 39% w/w is released about 2 hours after start of the test,
about 47% w/w is released about 3 hours after start of the test,
about 53-56% such as, e.g., about 53% w/w is released about 4 hours after start of the test,
about 66-72% such as, e.g., about 66% w/w is released about 6 hours after start of the test,
about 80-85% w/w is released about 8 hours after start of the test,
about 93% w/w is released about 10 hours after start of the test,
about 100% w/w is released about 12 hours after start of the test.
A still further release pattern of midodrine from a controlled release composition of a kit according to the inventionxe2x80x94when tested in vitro employing any of Dissolution Method I, II, III or IV as described hereinxe2x80x94is:
1-15% w/w is released from the composition within the first 30 min after start of the test,
10-35% (25%) w/w is released about 30 min after start of the test,
15-40% (35%) w/w is released about 1 hour after start of the test,
20-50% (39%) w/w is released about 2 hours after start of the test,
20-55% (47%) w/w is released about 3 hours after start of the test,
25-75% such as 25-65% (53%) w/w is released about 4 hours after start of the test,
30-74% (66%) w/w is released about 6 hours after start of the test,
35-85% (75%) w/w is released about 7 hours after start of the test,
45-95% (90%) w/w is released about 8 hours after start of the test,
65-100% (97%) w/w is released about 10 hours after start of the test,
90-110% (100%) w/w is released about 12 hours after start of the test.
Another suitable release pattern of midodrine from a controlled release composition of a kit according to the inventionxe2x80x94when tested in vitro employing any of Dissolution Method I, II, III or IV as described hereinxe2x80x94is:
1-15% w/w is released from the composition within the first 30 min after start of the test,
15-35% (25%) w/w is released about 30 min after start of the test,
20-40% (35%) w/w is released about 1 hour after start of the test,
25-50% (39%) w/w is released about 2 hours after start of the test,
30-55% (47%) w/w is released about 3 hours after start of the test,
40-75% such as, e.g., 40-65% (53%) w/w is released about 4 hours after start of the test,
50-74% (66%) w/w is released about 6 hours after start of the test,
60-85% (75%) w/w is released about 7 hours after start of the test,
70-95% (90%) w/w is released about 7 hours after start of the test,
80-100% (97%) w/w is released about 10 hours after start of the test,
90-110% (100%) w/w is released about 12 hours after start of the test.
In other aspects, the release pattern of midodrine from a controlled release composition of a kit according to the inventionxe2x80x94when tested in vitro employing any of Dissolution Method I, II, III or IV as described hereinxe2x80x94is as follows (xc2x130% w/w, xc2x120% w/w, xc2x110% w/w, xc2x17.5% w/w or xc2x15% w/w of the values stated below):
about 25% w/w is released about 30 min after start of the test,
about 35% w/w is released about 1 hour after start of the test,
about 39% w/w is released about 2 hours after start of the test,
about 47% w/w is released about 3 hours after start of the test,
about 53% w/w is released about 4 hours after start of the test,
about 66 w/w is released about 6 hours after start of the test,
about 75% w/w is released about 7 hours after start of the test,
about 80% w/w is released about 8 hours after start of the test,
about 90% w/w is released about 10 hours after start of the test,
about 100% w/w is released about 12 hours after start of the test, or
about 28% w/w is released about 30 min after start of the test,
about 35% w/w is released about 1 hour after start of the test,
about 41% w/w is released about 2 hours after start of the test,
about 45% w/w is released about 3 hours after start of the test,
about 55% w/w is released about 4 hours after start of the test,
about 70 w/w is released about 6 hours after start of the test,
about 78% w/w is released about 7 hours after start of the test,
about 90% w/w is released about 8 hours after start of the test,
about 95% w/w is released about 10 hours after start of the test,
about 100% w/w is released about 12 hours after start of the test.
As seen in the examples herein it is possible to obtain a release pattern. which corresponds to the above-mentioned values xc2x17.5% or xc2x15%.
In another aspect, the invention relates to a kit comprising a controlled release composition, wherein the release pattern of midodrine from the compositionxe2x80x94when tested in vitro employing any of Dissolution Method I, II, III or IV as described hereinxe2x80x94is as follows (xc2x130% w/w, xc2x120% w/w, xc2x110% w/w, xc2x17.5% w/w or xc2x15% w/w of the values stated below):
about 20% w/w is released about 30 min after start of the test,
about 20% w/w is released about 1 hour after start of the test,
about 20% w/w is released about 2 hours after start of the test,
about 20% w/w is released about 3 hours after start of the test
about 25% w/w is released about 4 hours after start of the test,
about 45 w/w is released about 6 hours after start of the test,
about 75% w/w is released about 7 hours after start of the test,
about 90% w/w is released about 8 hours after start of the test,
about 95% w/w is released about 10 hours after start of the test,
about 100% w/w is released about 12 hours after start of the test.
In those cases where the controlled release composition of a kit according to the invention contains desglymidodrine or a pharmaceutically acceptable salt thereof then the release pattern of desglymidodrine generally follows the patterns given above for midodrine.
If the controlled release composition of a kit according to the invention contains midodrine or a pharmaceutically acceptable salt thereof and desglymidodrine or a pharmaceutically acceptable salt thereof, then the release pattern of the sum of midodrine and desglymidodrine is calculated on a molar basis follows the patterns given above for midodrine.
As earlier discussed the release rate of midodrine (and/or desglymidodrine) is important in order to achieve a suitable release pattern. Thus, a controlled release composition of a kit according to the present invention normally has a release rate of midodrinexe2x80x94when tested in vitro employing any of Dissolution Method I, II, III or IVxe2x80x94that corresponds to a curve that has a shape corresponding to
i) a relatively fast first initial release followed by
ii) a steady release or a slower release than in step i) above, which is followed by
iii) a second rise in release rate and. finally,
iv) a decline in release rate.
In general, the second rise in release rate takes place 5-10 hours such as, e.g., about 5-9 hours, about 6-8 hours after start of the dissolution test, or 6.5-9 hours after start of the dissolution test simulating the time it takes to reach the colon after oral administration.
With respect to the steady release period, it normally starts about 1-3 hours after the start of the dissolution test, and the steady release is maintained for at least 2 hours such as, e.g. at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours such as about 6-8 hours.
More specifically, the release rate of midodrine (or desglymidodrine or the sum of midodrine and desglymidodrine on a molar basis) from a controlled release composition of a kit according to the inventionxe2x80x94when tested in vitro employing dissolution apparatus 2 (paddle) according to USP and Ph. Eur, 100 rpm, 0.1 N hydrochloric acid as dissolution medium or any of Dissolution Method I, II , III or IV as described herein and a temperature of 37xc2x0 C.xe2x80x94in %/hour is as follows (xc2x110-40% such as, e.g. xc2x110-30% or xc2x110%, xc2x115% or xc2x120% of the values stated below):
about 35%/hour about 30 min after start of the test(range e.g. 15-40%/hour),
about 12%/hour about 1 hour after start of the test (range e.g 4-15%/hour),
about 6%/hour about 2 hours after start of the test (range e.g. 2-10%/hour),
about 7%/hour about 3 hours after start of the test (range e.g. 2-10%/hour),
about 6.5%/hour about 4 hours after start of the test (range e.g. 2-15%/hour),
about 7.5%/hour about 6 hours after start of the test (range e.g. 2-30% such as, e.g., 2-10%/hour),
about 10%/hour about 8 hours after start of the test (range e.g. 2-15%/hour),
about 2%/hour about 10 hours after start of the test (range e.g. 0-10%/hour),
about 1%/hour about 12 hours after start of the test (range e.g. 0-10%/hour).
A controlled release composition of a kit according to the invention is normally suitable for administration once or twice daily, and it differs from a plain tablet composition, e.g. Gutron(copyright) tablets, in many ways. In the following is given pharmacokinetic values of importance for achievement of a prolonged therapeutic effect of a composition according to the invention. Further details concerning the definition of the parameters and the method of obtaining relevant values are given in Example 15 herein.
When tested as described in Example 15 herein, W50 of midodrine (defined as corresponding to the time the plasma concentration curve is or is above 50% of the Cmax value) is from about 1 to about 9 hours such as, e.g. from about 1.3 to about 8 hours such as, e.g. at least about 1.4 hours, at least about 1.5 hours, or at least about 1.7 hours.
Compared with a standard midodrine composition, W50 is increased with a factor of at least 2 such as, e.g., at least 2.5. A suitable comparison is performed against a plain Gutron(copyright) tablet administered in the same dose and W50 is determined from a plasma concentration versus time curve. The plasma concentration reflects the sum concentration in nmol/l of midodrine and desglymidodrine.
Analogously, W75, (T greater than 75% Cmax) is increased with a factor of at least 2 when compared with a plain Gutron(copyright) tablet administered in the same dose. W75 (T greater than 75% Cmax) is determined from a plasma concentration versus time curve and the plasma concentration reflects the sum concentration in nmol/l of midodrine and desglymidodrine.
Likewise, W50 of desglymidodrine (defined as corresponding to the time the plasma concentration curve is or is above 50% of the Cmax value) is from about 5 to about 12 hours such as, e.g. from about 6 to about 11 hours such as, e.g. at least about 7 hours.
Furthermore, Tmax is increased with a factor of at least 2 when compared with a plain Gutron(copyright) tablet administered in the same dose. Tmax is determined from a plasma concentration versus time curve and the plasma concentration reflects the sum concentration in nmol/l of midodrine and desglymidodrine.
MRT (mean residence time) is increased with a factor of at least 1.5 such as, e.g., at least 2, at least 2.5 or at least 3 when compared with a plain Gutron(copyright) tablet administered in the same dose. MRT is determined from a plasma concentration versus time curve and the plasma concentration reflects the sum concentration in nmol/l of midodrine and desglymidodrine.
MRT for midodrine is at least about 1.5 hours such as, e.g., at least about 2 hours, at least about 2.5 hours or at least about 3 hours, and/or MRT for desglymidodrine is at least about 6 hours such as, e.g., at least about 7 hours, at least about 7.5 hours, at least about 8 hours, at least about 8.5 hours, at least about 9 hours, or at least about 9.5 hours.
Active Drug Substances
As mentioned above, a kit according to the invention is suitable for use for any active drug sustance for which a dissolution pattern as described above is of relevance, and which beneficially can be administered only once or twice daily.
With respect to treatment of orthostatic hypotension and the other conditions mentioned above, midodrine and its active metabolite desglymidodrine are drugs of choice.
Midodrine as well as desglymidodrine exist in racemic form and in the form of the two enantiomeric species.
Midodrine is also known as ST 1085, or 2-amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]-acetamide. It may be in present in racemic form, i.e. as (xc2x1)-midodrine, (xc2x1)-ST 1085, or (xc2x1)-2-amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]-acetamide, (xc2x1)-2-amino-N-[2-2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]-acetamide, or in its enatiomeric form as (xe2x88x92)-midodrine, (R)-midodrine, (xe2x88x92)-ST 1085, (R)-ST 1085, (xe2x88x92)-2-amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]-acetamide, or (R)-2-amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]-acetamide, or in its other enantiomeric form (+)-midodrine or (S)-midodrine, (+)-ST 1085, or (S)-ST 1085, (+)-2-amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]-acetamide or (S)-2-amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]-acetamide.
Desglymidodrine is also known as ST 1059, alpha-(aminomethyl)-2,5-dimethoxy-benzenemethanol. It may be present in racemic form, i.e. as (xc2x1)-desglymidodrine, (xc2x1)-ST 1059 or (xc2x1)-alpha-(aminomethyl)-2,5-dimethoxy-benzenemethanol, or in its enantiomeric form as (xe2x88x92)-desglymidodrine, (R)-desglymidodrine, (xe2x88x92)-ST1059, (R)-ST1059, (xe2x88x92)-alpha-(aminomethyl)-2,5-dimethoxy-benzenemethanol or (R)-alpha-(aminomethyl)-2,5-dimethoxy-benzenemethanol, or in its other enatiomeric form (+)-desglymidodrine, (S)-desglymidodrine, (+)-ST1059(S)-ST1059(+)-alpha-(aminomethyl)-2,5dimethoxy-benzenemethanol or (S)-alpha-(aminomethyl)-2,5-dimethoxy-benzenemethanol.
A composition of a kit according to the invention may therefore include midodrine in the racemic form (RS), in the enantiomeric form (R), in the enantiomeric form (S) or in mixtures thereof.
In an embodiment according to the invention the kit comprises a composition which includes at least 90% w/w such as, e.g., at least 95% w/w, at least 97% w/w, at least 98% w/w, at least 99% w/w of midodrine in the therapeutically active enantiomeric form; and the therapeutically active enantiomeric form of midodrine is (xe2x88x92)-2-amino-N-(xcex2-hydroxy-2,5-dimethoxyphenethyl)-acetamide or the (R) form of midodrine.
In another embodiment according to the invention, a composition contains the active metabolite desglymidodrine (ST 1059), and desglymidodrine is present in the form of (xc2x1)-xcex1-(aminomethyl)-2,5-dimethoxy-benzenemethanol (xc2x1ST 1059), (+)-xcex1-(aminomethyl)-2,5-dimethoxy-benzenemethanol (+ST 1059), (xe2x88x92)-xcex1-(aminomethyl)-2,5-dimethoxy-benzenemethanol (xe2x88x92ST 1059) or mixtures thereof.
In a still further embodiment a composition of a kit according to the invention contains desglymidodrine in the racemic form (RS), in the enantiomeric form (R), in the enantiomeric form (S) or in mixtures thereof, or it contains at least 90% w/w such as, e.g., at least 95% w/w, at least 97% w/w, at least 98% w/w, at least 99% w/w of desglymidodrine is present in the therapeutically active enantiomeric form. The therapeutically active enantiomeric form of desglymidodrine is contemplated to be (xe2x88x92)-xcex1-(aminomethyl)-2,5-dimethoxy-benzenemethanol (xe2x88x92ST 1059) or the (R) form of desglymidodrine ((R) ST 1059).
In a composition according to the invention midodrine and/or desglymidodrine are present in the form of a pharmaceutically acceptable salt such as a salt formed between midodrine and/or desglymidodrine and an inorganic acid such as e.g., a hydrochloride, a hydrobromide, a hydroiodide, a nitrate, a nitrite, a H3PO3 salt, a H3PO4 salt, a H2SO3 salt, a sulfate, a H2SO5 salt, or a salt formed between midodrine and/or desglymidodrine and an organic acid such as organic acids like e.g. H2CO3, acetic acid, C2H5COOH, C3H7COOH, C4H9COOH, (COOH)2, CH2(COOH)2, C2H5(COOH)2, C3H6(COOH2, C4H3(COOH)2, C5H10(COOH)2, fumaric acid, maleic acid, lactic acid, tartaric acid, citri acid, ascorbic acid, benzoic acid, salicylic acid and phthalic acid
A composition according to the invention may comprise a further active drug substance, i.e. the composition may be in the form of a so-called combination composition comprising at least two different active drug substances. The further active drug substance may be any active drug substance, which beneficially is used in combination with midodrine and/or desglymidodrine. Interesting examples of further active drug substances are steroids like e.g. hydrocortisone or fludrocortisone or somatostin analogoues like e.g. octreotide.
Dosage
In general, the dosage of the active drug substance present in a composition according to the invention depends inter alia on the specific drug substance, the age and condition of the patient and of the disease to be treated.
A composition according to the present inventions aims at a dosage once or twice daily, preferably once daily. In the present context the term xe2x80x9conce dailyxe2x80x9d/xe2x80x9conce-a-dayxe2x80x9d is intended to mean that it is only necessary to administer the pharmaceutical composition once a day in order to obtain a suitable therapeutic and/or prophylactic response; however, any administration may comprise co-administration of more than one dosage unit such as, e.g. 2-4 dosage units.
In agreement with the above-mentioned definition of xe2x80x9conce dailyxe2x80x9d/xe2x80x9conce-a-dayxe2x80x9d, xe2x80x9ctwice dailyxe2x80x9d/xe2x80x9ctwice-a-dayxe2x80x9d is supposed to mean that it is only necessary to administer the controlled release composition of the kit at the most twice a day in order to obtain a suitable therapeutic and/or prophylactic response in the patient which can form a basis for an individual supply with the relatively fast onset composition.
Irrespective of the above-mentioned definitiones of xe2x80x9concexe2x80x9d and xe2x80x9ctwicexe2x80x9d daily, a dosage unit constructed to deliver the active ingredient after only one daily administration is preferred. However, due to individual circumstances some patients may need a new dosage after e.g. 7-18 hours such as, e.g. about 7-8 hours or about 12 or about 18 hours if the patient e.g. has abnormal absorption or bowel transit time. If the individual has a relatively fast bowel transit time, some of the active drug substance may be excreted before the full dosage is released.
With respect to midodrine, the normal daily dose is from 2.5 to 10 mg three or up to four times daily (calculated as midodrine hydrochloride), i.e. a daily dose of from about 7.5 mg to about 40 mg in the treatment of orthostatic hypertension. However, the daily dose in the treatment of urinary incontinence may be different and, accordingly, a composition according to the present invention typically contains from about 2.5mg to about 50 mg midodrine such as, e.g. 2.5 mg, 5 mg, 7.5 mg, 10 mg. 12.5 mg, 15 mg, 17.5 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg or 50 mg. In the cases, where midodrine is employed in another form e.g. in another salt form than midodrine hydrochloride, the above-mentioned dosage ranges are of course to be recalculated so that the same dosage is employed on a molar basis.
The total daily doses of midodrine will depend on the indication for the treatment and the individually tolerated doses. The kit of the present invention provides a possibility of a treatment regimen adapted for the specific patient
The individual fast onset doses of the kit of the invention may be from 0.2 mg to 10 mg, preferreably from 0.5 mg to 7.5 mg such as of 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 2 mg, 2.5 mg, 3mg, 4mg, or 5 mg.
As discussed above, midodrine may be present as the racemic form or in one of its enantiomeric forms, preferably the therapeutically active enantiomeric form. In those cases where midodrine is present in its therapeutically active enantiomeric form a reduction in the above-mentioned dosage ranges may be relevant.
With respect to the dosage in those cases where desglymidodrine is employed it is envisaged that the same dosages as mentioned above are relevant,
Formulation Techniques
In principle any relevant controlled formulation technique for preparing an oral controlled release composition may be applied. Thus, the dosage form may be in the form of a liquid having e.g. particles dispersed in a dispersion medium or it may be in the form of a single or a multiple unit dosage form intended for use as such as for dispersing in a dispersion medium before use
Any relevant formulation technique for preparing pharmaceutical compositions may be applied when formulating the relatively fast onset composition. A person skilled in the art of pharmaceutical formulation techniques can find guidance in the handbook Remington""s Pharmaceutical Sciences and in the Examples herein.
In the following is given a short review on general controlled release formulation techniques with an aim of obtaining the type of dissolution profile described above. In the compositions described below a person skilled in the art will know how to incorporate a part that gives rise to a relatively fast release of the active drug substance. As an example, such a part may be incorporated in an outermost coating layer comprising the active substance or it may be incorporated in the form of pellets formulated without retarding agents neither in the cores nor in a coating.
Examples of Different Controlled Release Technologies are
1, Single units
1.1 Coated matrix
1.2 Double or triple compression
1.3 Multilayer coating
2. Multiple units
2.1 Units having a controlled release coating
2.2 Units having a controlled release matrix
2.3 Units having a controlled release compression coating
2.4 Units with a multilayer coating.
Coated Matrix 
The idea behind the use of this technology is to coat a sparingly soluble and/or swellable polymer, in which midodrine (and/or any relevant substance such as, e.g. desglymidodrine) is embedded, with an insoluble diffusion barrier. The diffusion of midodrine is controlled by the matrix and the coat. This technique will cover the type of dissolution profile described in step 2 above.
If a soluble outer film layer containing midodrine is applied on the coated matrix, step 1 is achievable too.
Step 3 can be covered by including enteric coated units embedded in the matrix.
Double or Triple Compression
The basic idea for such a formulation is a core of a polymer having midodrine and/or desglymidodrine incorporated. This core is compression coated with a polymer with midodrine incorporated in the same or another concentration than in the core. When triple compression is employed, the coated core is compression coated once more with a polymer with midodrine in the same or another concentration as in the first coat Finally, the doble or triple compression unit is spray coated and midodrine is incorporated in the coat. However, the concentrations of midodrine in the different coats may vary markedly. The idea behind the multiple layers is that when the midodrine of the first layer has been almost depleted, the next layer takes over and levels out or changes the release profile. 
The spray coating with midodrine and/or desglymidodrine gives an immediate burst of the active compound.
Steps 1, 2 and 3 can be covered by use of this technique.
Multilayer Coating
The idea with this type of formulation is to coat an inert core with several layers of diffusion barriers, each barrier containing different concentrations of midodrine. The concentration should be highest in the inner coat and lowest in the outer coat
The purpose of the concentration gradient is to compensate for the increasing diffusion distance closer to the core. If the thickness of the diffusion barriers and the concentration gradients are correctly adjusted, steps 1, 2 and 3 will be obtainable.
Use of Enteric Coating
The correct start of step 3 in the triple compression and multilayer technologies might be optimized by the use of an enteric polymer.
Use of Amylose as Colon Degradable Excipient
The correct start of step 3 in the triple compression and multilayer technologies might also be optimized by the use of an amylose containing film coating such as a coating containing ethylcellulose and amylose or Eudragit RS and amylose.
Multiple Unit Systems
The units comprise pellets, granules, crystals, mini tablets or mixtures thereof.
Step 1 can be covered by an uncoated unit.
Step 2 can be covered by the application of a controlled release coating or by formulating the unit as a matrix or a coated matrix
Step 3 can be covered by the use of an enteric polymer or amylose, or by having units compressed as described in the triple compression technology.
In specific embodiments, a composition of a kit according to the invention is in the form of a solid dosage form such as, e.g., tablets, capsules, sachets, solid dispersion, crystals, granules and the like.
A controlled release composition of a kit according to the invention can also comprise at least two parts such as at least a first and a second part, each part contains midodrine and/or, if present, desglymidodrine and the first part being adapted to release midodrine and/or, if present, desglymidodrine, in a controlled manner during the first 0-14 such as, e.g. 0-11 hours after oral intake and the second part being adapted to release midodrine and/or, if present, desglymidodrine, starting at least 6 hours after oral intake.
In such a composition at least one of the at least two parts is present in the composition in the form of a multiplicity of individual units such as, e.g. pellets or minitablets.
The two parts of the at least two parts may also be present in the composition in the form of a multiplicity of individual units such as, e.g. pellets or minitablets, and the two parts may be in admixture.
A controlled release composition of a kit according to the invention may also be in multiple unit dosage form such as, e.g., wherein at least one of the at least two parts comprises at least two different types of pellets, the first type of pellets corresponding to a first fraction and the second type of pellets corresponding to a second fraction.
Moreover, the at least two parts of the controlled release composition may comprise at least two different types of pellets, the first type of pellets corresponding to the first part and the second type of pellets corresponding to the second part.
A controlled release composition of a kit according to the invention may also as individual units contain minitablets, i.e. be in the form of a multiple unit dosage form comprising at least two different types of minitablets, the first type of minitablets corresponding to the first part and the second type of minitablets corresponding to the second part. In the present context a minitablet is a tablet having a size in a range corresponding to from about 0.7 mm to about 7 mm in diameter such as, e.g., in a range corresponding to from about 1 to about 7 mm, from about 1.5 to about 6 mm, from about 2 mm to about 5 mm, from about 2 mm to about 4 mm such as in a range corresponding to from about 2 to about 3 mm in diameter.
A controlled release composition of a kft according to the invention may also as individual units contain relatively large crystals of the active drug substance. In such cases, the size of the unit is at the most about 1 mm such as, e.g., in a range corresponding to from about 0.1 to about 1 mm, from about 0.2 mm to about 0.8 mm, from about 0.2 mm to about 0.7 mm or from about 0.3 mm to about 0.7 mm.
A controlled release composition of a kit according to the invention may be in the form of a multiple unit dosage form, wherein the first or the second part is in the form of minitablets, in the form of pellets or in the form of large crystals of the active drug substance.
Moreover, at least two fractions may be present in a tablet such as, e.g. a multilayer tablet and the at least first and the second part are each comprised in a layer in the tablet.
Furthermore, a composition of a kit according to the invention may comprise a third part adapted to release midodrine and, if present, desglymidodrine relatively fast from the composition and/or a fourth part adapted to release midodrine and/or desglymidodrine from the composition 6-10 hours after oral intake.
In one embodiment the third and/or, if present, the fourth part comprise pellets or minitablets or are a layer in a tablet.
With respect to release kinetics, a controlled release composition of a kit according to the invention may have a first part, a second part a third part and/or a fourth part which have a release kinetic corresponding to a zero or a first order release or a mixture of zero and first order release. Other orders of release may be 1.5, 2, 3 or 4.
All the above-mentioned combinations of different types of compositions or formulation techniques apply, whenever relevant, mutatis mutandi to the fast release part or composition of the kit of the invention. The same applies to the combination of the controlled release part or composition and the fast release part or composition of a kit of the invention
Pharmaceutically Acceptable Excipients
Apart from the active drug substance in the composition, a pharmaceutical composition according to the invention may further comprise pharmaceutically acceptable excipients.
In the present context, the term xe2x80x9cpharmaceutically acceptable excipientxe2x80x9d is intended to denote any material, which is inert in the sense that it substantially does not have any therapeutic and/or prophylactic effect per se. A pharmaceutically acceptable excipient may be added to the active drug substance with the purpose of making it possible to obtain a pharmaceutical composition, which has acceptable technical properties
Fillers/diluents/binders may be incorporated such as sucrose, sorbitol, mannitol, lactose (e.g., spray-dried lactose, xcex1-lactose, xcex2-lactose, Tabletose(copyright), various grades of Pharmatose(copyright), Microtose or Fast-Floc(copyright)), microcrystalline cellulose (e.g., various grades of Avicel(copyright), such as Avicel(copyright) PH101, Avicel(copyright) PH102 or Avicel(copyright) PH105, Elcema(copyright) P100, Emcocel(copyright), Vivacel(copyright), Ming Tai(copyright) and Solka-Floc(copyright)), hydroxypropylcellulose, L-hydroxypropylcellulose (low-substituted) (e.g. L-HPC-CH31, L-HPC-LH11, LH 22, LH 21, LH 20, LH 32, LH 31, LH30), dextrins, maltodextrins (e.g. Lodex(copyright) 5 and Lodex(copyright) 10), starches or modified starches (including potato starch, maize starch and rice starch), sodium chloride, sodium phosphate, calcium phosphate (e.g. basic calcium phosphate, calcium hydrogen phosphate), calcium sulfate, calcium carbonate, gelatine, polyvinylpyrrolidone (30, 90, Kollidon VA 64), and sodium carboxymethylcellulose.
Disintegrants may be used such as cellulose derivatives, including microcrystalline cellulose, low-substituted hydroxypropyl cellulose (e.g. LH 11, H 22, LH 21, LH 20, LH 32, LH 31, LH30); starches, including potato starch; croscarmellose sodium (i.e. cross-linked carboxymethylcellulose sodium salt; e.g. Ac-Di-Sol(copyright)): alginic acid or alginates; insoluble polyvinylpyrrolidone (e.g. Polyvidon(copyright) CL, Polyvidon(copyright) CL-M, Kollidon(copyright) CL, Polyplasdone(copyright) XL, Polyplasdone(copyright) XL-10); sodium carboxymethyl starch (e.g. Primogel(copyright)) and Explotab(copyright)).
Glidants and lubricants may be incorporated such as stearic acid, metallic stearates, talc, waxes and glycerides with high melting temperatures, colloidal silica, sodium stearyl fumarate, polyethylenglycols and alkyl sulphates.
Surfactants may be employed such as non-ionic (e.g., polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85, polysorbate 120, sorbitane monoisostearate, sorbitanmonolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, glyceryl monooleate and polyvinylalkohol), anionic (e.g., docusate sodium and sodium lauryl sulphate) and cationic (e.g., benzalkonium chloride, benzethonium chloride and cetrimide) or mixtures thereof. Examples of amphoteric surfactants are 1,2-diacyl-L-phosphatidylcholine, N-lauryl-N,N-dimethylglycine, alkylaminopropionic acid, alkyliminodipropionic acid, and dimethyl-(3-palmitamidopropyl)-aminoacetate.
Other appropriate pharmaceutically acceptable excipients may include colorants, flavouring agents, pH adjusting agents, solubilizing agents, wetting agents and buffering agents
Modified Release Coating
A unit comprised in a composition according to the invention may be coated with a modified release coating.
The modified release coating is a substantially water-insoluble but water-diffusible coating.
The modified release coating may be applied on the multiple units or on the single units from a solution and/or suspension preferably in an aqueous solvent, but an organic coating composition may also be applied. The modified release coating may also be applied as a compression coating comprising a dry mixture of polymer(s) and the e.g. the active drug substance.
Examples of matrix-forming agents are hydroxypropylmethylcellulose such as, e.g., 1828, 2208, 2906 or 2910 according to USP, hydroxypropylcellulose, micronised ethylcellulose, low-substituted hydroxypropylcellulose (LH 20, 21, 31).
Examples of film-forming agents which are suitable for use in accordance with the present invention are agents selected from the group consisting of cellulose derivatives such as, e.g., ethylcellulose, cellulose acetate, cellulose propionate, cellulose butyrate, cellulose valerate, cellulose acetate propionate; acrylic polymers such as, e.g., polymethyl methacrylate; vinyl polymers such as, e.g., polyvinyl acetate, polyvinyl formal, polyvinyl butyryl, vinyl chloride-vinyl acetate copolymer, ethylene-vinyl acetate copolymer, vinyl chloride-propylene-vinyl acetate copolymer; silicon polymers such as, e.g., ladder polymer of sesquiphenyl siloxane, and colloidal silica; polycarbonate: polystyrene; polyester; cournarone-indene polymer; polybutadiene; and other high molecular synthetic polymers.
In certain preferred embodiments, the acrylic polymer is comprised of one or more ammonio methacrylate copolymers. Ammonio methacrylate copolymers are well known in the art, and are described in NF XVII as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups.
In one preferred embodiment, the acrylic coating is an acrylic resin lacquer used in the form of an aqueous dispersion, such as that which is commercially available from Rohm Pharma under the tradename Eudragit(copyright). In further preferred embodiments, the acrylic coating comprises a mixture of two acrylic resin lacquers commercially available from Rohm Pharma under the tradenames Eudragit(copyright) RL 30 D and Eudragit(copyright) RS 30 D, re-spectively. Eudragit(copyright) RL 30 D and Eudragit(copyright) RS 30 D are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters being 1:20 in Eudragit(copyright) RL 30 D and 1:40 in Eudragit(copyright) RS 30 D. Eudragit(copyright) RL/RS mixtures are insoluble in water and in digestive fluids. However, coatings formed from the same are swellable and permeable in aqueous solutions and digestive fluids, The Eudragit(copyright) RL/RS dispersions may be mixed together in any desired ratio in order to ultimately obtain a modified release formulation having a desirable dissolution profile. The most desirable modified release formulations may be obtained from a retardant coating based on Eudragit(copyright) NE 30D, which is a neutral resin having a molecular weight of 800,000.
Examples of enteric polymers are cellulose acetate phthalate, cellulose acetate trimellitate, hydroxy propyl methyl cellulose acetate phthalate, hydroxy propyl methyl cellulose acetate succinate, carboxy methyl ethyl cellulose, polyvinyl acetate phthalate, copolymer of vinyl acetate and crotonic acid and poly(methacrylic acid, ethacrylate), and Eudragit(copyright) S 12.5, Eudragit(copyright) 100, Eudragit(copyright) FS 30D (all from Rxc3x6hm) Sureteric(copyright) (from Colorcom), Aquateric(copyright) (from FMC) or HPMCP (from Shin-Etsu).
The amount of coating applied is adapted so as to obtain a predetermined dissolution characteristic of the composition
However, the amount of coating applied should also be adapted so that there will be no rupturing problems.
The coating may be admixed with various excipients such as plasticizers, anti-adhesives such as, e.g., colloidal silicium dioxide, inert fillers, lipophilic agents such as, e.g. stearic acid, capric acid or hydrogenated castor oil, colon targeting excipients such as, e.g. amylose, ethylcellulose, Eudragit S 12.5 etc., and pigments in a manner known per se.
Tackiness of the water-dispersible film-forming substances may be overcome by simply incorporating an anti-adhesive in the coating. The anti-adhesive is preferably a finely divided, substantially insoluble, pharmaceutically acceptable non-weting powder having anti-adhesive properties in the coating. Examples of anti-adhesives are metallic stearates such as magnesium stearate or calcium stearate, microcrystalline cellulose, or mineral substances such as calcite, substantially water-insoluble calcium phosphates or substantially water-insoluble calcium sulphates, colloidal silica, titanium dioxide, barium sulphates, hydrogenated aluminium silicates, hydrous aluminium potassium silicates and talc. The preferred anti-adhesive is talc. The anti-adhesive or mixture of anti-adhesives is preferably incorporated in the coating in an amount of about 0.1-70% by weight, in particular about 1-60% by weight, and preferably about 50% by weight of the film layer. By selecting a small particle size of the talc, a larger surface area is obtained; the consequent higher anti-adhesive effect makes it possible to incorporate smaller amounts of specific anti-adhesives.
The units may further comprise an outer film layer.
In one aspect, the outer second layer comprises a water-based film-forming agent which prevents adhesion between the units at elevated temperatures and imparts flowability to the units, the water-based film-forming agent being anti-adhesive at temperatures above about 40xc2x0 C., especially temperatures above abut 50xc2x0 C., such as a temperature between about 60xc2x0 C. and about 120xc2x0 C., and being selected from diffusion coating materials such as ethylcellulose or enteric coating materials such as anionic poly(meth)acrylic acid esters, hydroxypropylmethylcellulosephthalate, celluloseacetatephthalate, polyvinyl-acetatephthalate, polyvinylacetatephthalate-crotonic acid copolymerisates, or mixtures hereof, or water-soluble coating materials such as water-soluble cellulose derivatives, e.g. hydroxypropylcellulose, carboxymethylcellulose, methylcellulose, propylcellulose, hydroxyethylcellulose, carboxyethylcellulose, carboxymethylhydroxyethylcellulose, hydroxymethylcellulose, carboxymethylethylcellulose, methylhydroxypropylcellulose or hydroxypropylmethylcellulose.
Examples of plasticizers for use in accordance with the present invention include triacetin, acetylated monoglyceride, rape oil, olive oil, sesame oil, acetyl trbutyl citrate, acetyl triethyl citrate, glycerin, sorbitol, diethyloxalate, diethylmalate, diethylmaleate, diethylfumarate, diethylsuccinate, diethylmalonate, dioctylphthalate, dibutylsebacetate, triethylcitrate, tributylcitrate, glyceroltributyrate, polyethyleneglycol, propyleneglycol, 1,2-propyleneglycol, dibutylsebacate, diethylsebacate and mixtures thereof. The plasticizer is normally incorporated in an amount of less than 20% by weight, calculated on the dry matter content of the coating composition.
The fast onset composition of a kit according to the invention may be any composition well known in the art to provide a relative fast release.
With respect to nasal vehicles, polyethyleneglycols is especially preferred such as more n-ethylene glycols represented by the following formula
H(OCH2CH2)pOH
wherein p is an integer in the range of 1 to 14. Examples of n-ethylene glycols are monoethylene glycol (1EG), di ethylene glycol (2EG), triethylene glycol (3EG), tetraethylene glycol (4EG), penta ethylene glycol (5EG), hexaethylene glycol (6EG), heptaethylene glycol (7EG), octaethylene glycol (8EG), nonaethylene glycol (9EG), decaethylene glycol (10EG), undecaethylene glycol (11EG), dodecaethylene glycol (12EG), tridecaethylene glycol (13EG), and tetradecaethylene glycol (14EG). The ethylene glycols may be used in the form of the single compounds or as a mixture of two or more n-ethylene glycols, e.g. commercial products such as polyethylene glycol 200 (PEG 200), polyethylene glycol 300 (PEG 300) or polyethylene glycol 400 (PEG 400). The polyethyleneglycols may be used in combination with glycofurols (xcex1-[(tetrahydro-2-furany)methyl]-xcfx89-hydroxy-poly(oxy-1,2-ethanediyl)). The latter may also be used separately.
The volume of a nasal dosage is preferably within 500 xcexcl such as within 300 xcexcl such as in a range of 10-250 xcexcl.